Catalytic innovation underlies independent recruitment of polyketide synthases in cocaine and hyoscyamine biosynthesis

Tian Tian, Yong-Jiang Wang, Jian-Ping Huang, Jie Li, Bingyan Xu, Yin Chen, Li Wang, Jing Yang, Yijun Yan and Sheng-Xiong Huang ()
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Tian Tian: Chinese Academy of Sciences
Yong-Jiang Wang: Chinese Academy of Sciences
Jian-Ping Huang: Chinese Academy of Sciences
Jie Li: Chinese Academy of Sciences
Bingyan Xu: Chinese Academy of Sciences
Yin Chen: Chinese Academy of Sciences
Li Wang: Chengdu University of Traditional Chinese Medicine
Jing Yang: Chinese Academy of Sciences
Yijun Yan: Chinese Academy of Sciences
Sheng-Xiong Huang: Chinese Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-8

Abstract: Abstract Tropane alkaloids such as hyoscyamine and cocaine are of importance in medicinal uses. Only recently has the hyoscyamine biosynthetic machinery become complete. However, the cocaine biosynthesis pathway remains only partially elucidated. Here we characterize polyketide synthases required for generating 3-oxo-glutaric acid from malonyl-CoA in cocaine biosynthetic route. Structural analysis shows that these two polyketide synthases adopt distinctly different active site architecture to catalyze the same reaction as pyrrolidine ketide synthase in hyoscyamine biosynthesis, revealing an unusual parallel/convergent evolution of biochemical function in homologous enzymes. Further phylogenetic analysis suggests lineage-specific acquisition of polyketide synthases required for tropane alkaloid biosynthesis in Erythroxylaceae and Solanaceae species, respectively. Overall, our work elucidates not only a key unknown step in cocaine biosynthesis pathway but also, more importantly, structural and biochemical basis for independent recruitment of polyketide synthases in tropane alkaloid biosynthesis, thus broadening the understanding of conservation and innovation of biosynthetic catalysts.

Date: 2022
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DOI: 10.1038/s41467-022-32776-1

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